Interleukin-13 Induction of 15-Lipoxygenase Gene Expression Requires p38 Mitogen-Activated Protein Kinase-Mediated Serine 727 Phosphorylation of Stat1 and Stat3

Xu, Bo; Bhattacharjee, A.; Roy, Biswajit; Xu, Hong; Anthony, David G.; Frank, David A.; Feldman, Gerald M.; Cathcart, Martha K.

doi:10.1128/mcb.23.11.3918-3928.2003

Cited by 82 publications

(85 citation statements)

References 66 publications

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“…2, C and D) in vitro. Although, in vivo p38 MAPK inhibition could not regress the collagen induction process in this study, there are reports indicating the role of p38 MAPK signaling in serine phosphorylation of STAT proteins, which could be another possible mechanism by which MAPK affects the collagen induction process during hypertrophy (14,15,18). Again, several studies have established the role of ERK1/2 signaling in development of cardiac hypertrophy (55,56), corroborating our result that has shown prominent ERK1/2 activation in vitro (supplemental Fig.…”

Section: Discussionmentioning

confidence: 58%

Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) Attenuates Interleukin-6 (IL-6)-induced Collagen Synthesis and Resultant Hypertrophy in Rat Heart

Mir

Chatterjee

Mitra

et al. 2012

Journal of Biological Chemistry

126

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IL-6 has been shown to play a major role in collagen up-regulation process during cardiac hypertrophy, although the precise mechanism is still not known. In this study we have analyzed the mechanism by which IL-6 modulates cardiac hypertrophy. For the in vitro model, IL-6-treated cultured cardiac fibroblasts were used, whereas the in vivo cardiac hypertrophy model was generated by renal artery ligation in adult male Wistar rats (Rattus norvegicus). During induction of hypertrophy, increased phosphorylation of STAT1, STAT3, MAPK, and ERK proteins was observed both in vitro and in vivo. Treatment of fibroblasts with specific inhibitors for STAT1 (fludarabine, 50 M), STAT3 (S31-201, 10 M), p38 MAPK (SB203580, 10 M), and ERK1/2 (U0126, 10 M) resulted in down-regulation of IL-6-induced phosphorylation of specific proteins; however, only S31-201 and SB203580 inhibited collagen biosynthesis. In ligated rats in vivo, only STAT3 inhibitors resulted in significant decrease in collagen synthesis and hypertrophy markers such as atrial natriuretic factor and ␤-myosin heavy chain. In addition, decreased heart weight to body weight ratio and improved cardiac function as measured by echocardiography was evident in animals treated with STAT3 inhibitor or siRNA. Compared with IL-6 neutralization, more pronounced down-regulation of collagen synthesis and regression of hypertrophy was observed with STAT3 inhibition, suggesting that STAT3 is the major downstream signaling molecule and a potential therapeutic target for cardiac hypertrophy.Cardiac fibrosis is considered to be a major player during hypertrophy, where excess synthesis and a disproportionate accumulation of extracellular matrix proteins in the myocardium leads to its stiffness and diastolic dysfunction, leading to heart failure (1-3). Fibrillar collagen 1 and collagen 3 are the most abundant extracellular matrix proteins in the myocardium that maintain myocardial structural integrity (4). Collagen biosynthesis process is mainly compartmentalized in cardiac fibroblasts with a continuous turnover of newly synthesized collagen and degradation of old existing collagen, which involves post-transcriptional as well as post translational events. A physiological balance exists between collagen synthesis and degradation that is necessary to maintain tissue integrity of the myocardium. Extracellular catalytic cleavage of collagen is mediated by matrix metalloproteinases (MMPs) 2 that are eventually regulated by their naturally occurring endogenous inhibitors, i.e. tissue inhibitors of metalloproteinases (TIMPs) (1, 5).The fine balance between MMPs and TIMPs plays a crucial role in regulation of cardiac collagen turnover (5, 6). Furthermore, lysyl oxidase (LOX) is also instrumental during collagen biogenesis that catalyzes lysine-derived cross-bridges between two or more lysine residues of nascent procollagen peptides during their maturation into collagen molecules (5, 7). Altered and deregulated expression of these factors has been demonstrated in failing myocardium (5).Involvem...

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Section: Discussionmentioning

confidence: 58%

Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) Attenuates Interleukin-6 (IL-6)-induced Collagen Synthesis and Resultant Hypertrophy in Rat Heart

Mir

Chatterjee

Mitra

et al. 2012

Journal of Biological Chemistry

126

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“…Downstream targets of p38 MAPK in immune and endothelial cells or cell lines include transcription factors such as CREB (Gustin et al, 2004;Nemeth et al, 2003) and STAT1 and STAT3 (Goh et al, 1999;Xu et al, 2003). To determine if the signal transduction pathway activated by CCL2 in the hippocampal cultures involves these transcription factors, we determined the relative level of phosphorylation and therefore activation of these proteins in control and CCL2-treated cultures using Western blots analysis and phospho-specific antibodies.…”

Section: Ccl2 Activates Creb In Hippocampal Culturesmentioning

confidence: 99%

The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells

Cho

Gruol

2008

Journal of Neuroimmunology

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Emerging evidence indicates that chemokines can regulate both the physiology and biochemistry of CNS neurons and glia. In the current study, Western blot analysis showed that in rat hippocampal neuronal/glial cultures the signal transduction pathway activated by CCL2, a chemokine expressed in the normal brain and at elevated levels during neuroinflammation, involves a G-protein coupled receptor, p38 MAPK as well as its immediate upstream kinase MKK3/6, and the downstream transcription factor CREB. ERK 1/2 and the transcription factors STAT1 and STAT3 do not play a prominent role. CCL2 also altered Ca 2+ influx and synaptic network activity in the hippocampal neurons. These results suggest an important role for p38 MAPK and CREB in hippocampal actions of CCL2.

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“…Recently it was determined that the lipoxygenase gene Alox15, which encodes 12/15-LO, acts as a negative regulator of bone mineral density and thereby regulates the development of osteoporosis (7). 15-LO is not expressed in circulating monocytes, but upon exposure to IL-13, 15-LO expression increases dramatically (8,9). Our laboratory thus focused on understanding the regulation of IL-13-stimulated 15-LO expression in primary monocytes.…”

mentioning

confidence: 99%

Monocyte 15-Lipoxygenase Expression Is Regulated by a Novel Cytosolic Signaling Complex with Protein Kinase C δ and Tyrosine-Phosphorylated Stat3

Bhattacharjee

Frank

et al. 2006

The Journal of Immunology

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Our previous studies demonstrated that IL‐13‐induced 15‐lipoxygenase (15‐LO) expression in human monocytes is regulated by the activation of both Stat1 and Stat3 and by PKCδ. IL‐13 stimulated the phosphorylation of Stat3 on both Tyr705 and Ser727. In this study we show that IL‐13 induces the association of PKCδ with Stat3, not with Stat1, and is required for Stat3S727 phosphorylation. We found that the IL‐13‐dependent, novel signaling complex of PKCδ and Stat3 occurs almost exclusively in the cytosol and that the Stat3 in the complex is tyrosine phosphorylated. From our preliminary results we hypothesized that tyrosine phosphorylation was required for Stat3 interaction with PKCδ and subsequent PKCδ‐dependent phosphorylation of Stat3S727. Using an efficient transfection protocol for human monocytes, we showed that expression of Stat3 containing a mutation in Y705 inhibited the association of PKCδ with Stat3 and blocked Stat3S727 phosphorylation whereas transfection with wild‐type Stat3 did not. Our results indicate that Stat3Y705 phosphorylation is a prerequisite for the IL‐13–stimulated association of Stat3 with cytosolic PKCδ and the Stat3S727 phosphorylation. Furthermore, by transfecting monocytes with Stat3 containing mutations in Y705 and S727 or with wild type Stat3, we demonstrated that both Stat3 tyrosine and serine phosphorylations are required for optimal binding of Stat3 with DNA as well as for maximal expression of 15‐LO, an important regulator of inflammation and apoptosis. (This work was funded by HL51068)

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Interleukin-13 Induction of 15-Lipoxygenase Gene Expression Requires p38 Mitogen-Activated Protein Kinase-Mediated Serine 727 Phosphorylation of Stat1 and Stat3

Cited by 82 publications

References 66 publications

Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) Attenuates Interleukin-6 (IL-6)-induced Collagen Synthesis and Resultant Hypertrophy in Rat Heart

Inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) Attenuates Interleukin-6 (IL-6)-induced Collagen Synthesis and Resultant Hypertrophy in Rat Heart

The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells

Monocyte 15-Lipoxygenase Expression Is Regulated by a Novel Cytosolic Signaling Complex with Protein Kinase C δ and Tyrosine-Phosphorylated Stat3

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